Hepatitis A virus (HAV), a picornavirus, is the causative agent of acute hepatitis. Like other picornaviruses, HAV is assumed to enter the cell by first binding to a specific cellular receptor. Interaction of HAV with its cellular receptor could be responsible for many characteristics of HAV such as growth restriction in primate cells and hepatovirulence. Therefore, study of the interaction of HAV with its cellular receptor will help to understand the mechanisms involved in the pathogenicity of this virus and specific receptor antagonists could be useful therapeutic agents. Furthermore, identification of the HAV cellular receptor may lead to the development of small animal models for HAV infection. Such a model would b important for the testing of potency of future HAV vaccines. A monoclonal antibody to the surface of primary AGMK cells has been provided by Moritsug of Japan NIH. This antibody may be directed toward a receptor for HAV on some cells as it blocks HAV infection. The cDNA for this receptor is being cloned. Nonprimate cell lines that cannot be infected directly with HAV but are capable of supporting HAV replication upon transfection of genomic RNA. For the first time several non-primate cell lines (mouse, guinea pig, dolphin, pig, turtle) have been infected by HAV and one may meet the needs of a transfectable non-infectable cell line. As a result of this work, a guinea pig model for HAV is being tested. If a non-infectable but transfectable cell line is confirmed, DNA from a permissive cell line will be transfected in order to clone the major receptor. We are also raising monoclonal antibodies against permissive cell surface molecules and analyzing whether such antibodies could protect susceptible cells against HAV infection. Once we obtained such a protective MoAb, we will be able to characterize these cell surface molecules that could act as cellular receptors for HAV and molecularly clone them. Such MoAbs have not yet been identified.